Chronic viral infections afflict more than 500 million people worldwide. Loss of T cell function has been noticed for long time during persistent viral infections but the underlying factors are not completely understood. By using in vivo chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, we recently found that specific and exclusive attenuation of TGF? signaling on CD4 and CD8 T cells allows the generation of a powerful and functional T cell response in vivo. Remarkably, elimination of the virus is rapidly achieved and memory T cells emerge. These findings are significant and therapeutically relevant since the effects of reducing TGF? signaling are profound. However, understanding the cellular and molecular factors underlying the role of TGF? during viral persistence is essential for manipulating this pathway to boost anti-viral defense with minimal side effects. In this proposal, we plan to dissect TGF? biology in the context of a chronic viral infection. We will examine the cell source responsible for TGF? production as well as the factors regulating TGF? activation, a required step to expose the bioactive form of this molecule. We will also determine the direct and indirect effects of TGF? on CD4 and CD8 T cells and their link to other inhibitory pathways previously described. Finally, we will evaluate the potential of TGF? inhibition in vivo to eradicate an early-stage or fully established persistent infection. Our recent findings identify TGF? as a novel inhibitory molecule responsible for T cell exhaustion and viral persistence in vivo. These observations yield promising novel opportunities to be considered for devising new immunotherapies and deserve further study to harness the greatest potential of this pathway to cure or alleviate human chronic viral diseases without causing immunopathology. PUBLIC HEALTH RELEVANCE: Viruses that cause chronic infections, including Human Immunodeficiency virus (HIV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV), infect more than 500 million people worldwide and represent a major health problem. Progression to chronic phase has been associated with loss of T cell function (i.e. exhaustion) through multiple and conserved inhibitory pathways that appear to be shared between distinct chronic viral infections in different hosts. This proposal is focused on the study of a novel inhibitory pathway responsible for viral persistence in vivo, its contextual linkage with other known immunosuppressive pathways and its therapeutic potential for eradicating a chronic viral infection.